Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque E X, Zerlin M
Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, Mainz, Germany.
Biol Psychiatry. 2001 Feb 1;49(3):279-88. doi: 10.1016/s0006-3223(00)01109-4.
Cholinesterase inhibitors are the only approved drug treatment for patients with mild to moderately severe Alzheimer's disease. Interestingly, the clinical potency of these drugs does not correlate well with their activity as cholinesterase inhibitors, nor is their action as short lived as would be expected from purely symptomatic treatment. A few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated. These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. We have recently discovered a mechanism that could account, at least in part, for the above-mentioned unexpected properties of some cholinesterase inhibitors. We have found that a subgroup of cholinesterase inhibitors, including galantamine but excluding tacrine, directly interacts with nicotinic acetylcholine receptors. These compounds, named allosterically potentiating ligands, sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization. The allosterically potentiating ligand action, which is not necessarily associated with cholinesterase inhibition, has been demonstrated by whole-cell patch-clamp recordings to occur in natural murine and human neurons and in murine and human cell lines expressing various subtypes of neuronal nicotinic acetylcholine receptors.
胆碱酯酶抑制剂是唯一被批准用于治疗轻度至中度阿尔茨海默病患者的药物。有趣的是，这些药物的临床效力与其作为胆碱酯酶抑制剂的活性并无很好的相关性，而且它们的作用持续时间也不像单纯的对症治疗所预期的那样短暂。一些胆碱酯酶抑制剂，包括加兰他敏，即使在药物治疗终止后仍能产生有益效果。这些作用呈现出除单纯酯酶抑制之外的作用模式，并且能够引起全身变化。我们最近发现了一种机制，至少可以部分解释某些胆碱酯酶抑制剂上述出人意料的特性。我们发现，包括加兰他敏但不包括他克林在内的一组胆碱酯酶抑制剂可直接与烟碱型乙酰胆碱受体相互作用。这些化合物被称为变构增强配体，通过增加乙酰胆碱和烟碱型激动剂诱导的通道开放概率以及减缓受体脱敏来使烟碱型受体敏感化。全细胞膜片钳记录已证明，变构增强配体的作用不一定与胆碱酯酶抑制相关，在天然小鼠和人类神经元以及表达各种亚型神经元烟碱型乙酰胆碱受体的小鼠和人类细胞系中都会发生。
